The extent of intracellular polymerization of hemoglobin S is primarily determined by oxygen saturation, hemoglobin concentration and hemoglobin composition. We have examined the filterability of subpopulations of sickle erythrocytes to determine the possible extent of sickle hemoglobin polymer formation at arterial oxygen saturation which might adversely affect cell deformability. Progressive reduction of oxygen tension within the arterial range caused a sudden loss of filterability of sickle erythrocytes through 5 micron diameter pores at a critical p02, particularly in the dense cell fraction. This loss of filterability was reversible upon reoxygenation and occurred at a higher p02 than did morphological sickling. Impairment of erythrocyte filterability at high oxygen saturation suggests that small changes in oxygen saturation within the arterial circulation cause rheological impairment of sickle cells. It has been appreciated that fetal hemoglobin has a specific "sparing" effect in inhibiting polymerization of sickle hemoglobin, however, the exact amounts of fetal hemoglobin necessary to ameliorate the various manifestations of the sickle cell syndromes have been uncertain. Epidemiological analyses of sickle cell disease severity and studies of the biophysics of intracellular polymerization were used to estimate potential clinical benefit of various levels of fetal hemoglobin, of increases in hemoglobin S solubility and of decreases in intracellular hemoglobin concentration for use as guideposts for therapeutic goals. Erythrocytes containing hemoglobin Setif can undergo pseudosickling in the laboratory when incubated under select buffer conditions. Aggregation of hemoglobin lysate from these erythrocytes was detected when incubated in phosphate buffered saline at either 290 mOsm or 459 mOsm. The solubility of the lysate increased at 4 degrees C and the tendency for sickling decreased. Detailed studies of hemoglobin Setif aggregation may suggest alternate strategies of the inhibition of sickle hemoglobin aggregation.